Tissue injury results in the release of a diverse group of inflammatory mediators that sensitize nociceptors and spinal nociceptive neurons to mechanical and thermal stimuli, leading to heightened pain transmission. Local, systemic, or neurogenic release of inflammatory mediators include K+, neuropeptides, such as substance P, peptides such as bradykinin, cytokines, monoamines, and ATP, which activate or sensitize peripheral nociceptors. Furthermore, peripheral sensitization of nociceptors can, in turn, lead to central sensitization in the spinal cord, producing secondary hyperalgesia and allodynia through processes that include activation of NMDA.
Pain is currently considered to fall into three categories: nociceptive pain, activated by noxious stimuli on specialized receptors called nociceptors, inflammatory pain, in which damage to tissue causes release of inflammatory mediators, some of which directly activate nociceptors and others of which act to sensitive the somatosensory nervous system until the tissue heals, and neuropathic pain, in which damage or malfunction of peripheral or central nerves creates spontaneous pain with no protective or reparative role. See, Scholz and Woolf, Nature Neuroscience (Supp.) 5:1062-1067 (2002); Julius and Basbaum, Nature 413:203-210 (2001).
Long chain fatty acids, prominently arachidonic acid (“AA”), are molecules that lie at a pivotal point of important inflammatory cascades that result in peripheral sensitization of nociceptors. AA release activates two classes of enzymes: the cyclooxygenases (COX) and the lipoxygenases, which lead to the production of pro-inflammatory mediators including prostaglandins (PG) and leukotrienes. These enzymes have been the focus of intense research during the last decades, and inhibitors of these enzymes are major therapeutic agents for inflammatory pain. Another branch of the arachidonate cascade is the cytochrome P450-catalyzed conversion of AA and linoleic acid (LA). to a conspicuous group of metabolites including epoxyeicosatrienoic acid (EET), hydroxyeicosatrienoic acids (HETEs) and epoxyoctadecenoic acids (EpOMEs). Among these metabolites, EET is the putative endothelium-derived hyperpolarization factor, which exerts anti-inflammatory and antihypertensive effects in the cardiovascular system. EETs and EpOMEs are short-lived AA and LA metabolites that are converted by the enzyme soluble epoxide hydrolase (“sEH”) to pro-inflammatory dihydroeicosatrienoic acids (DHETs) and dihydroxyoctadecenoic acids (DiHOMEs), respectively. Inhibition of sEH increases detectable concentrations of EETs, decreasing blood pressure only under hypertensive conditions and reducing vascular inflammatory responses.
It would be useful to have additional agents which can be used for pain relief, particularly as topical agents.